The genomes of all organisms are susceptible to continuous deleterious mutations. The rate (U) at which deleterious mutations occur in the genome per generation and the distribution of their effects have important implications for the improvement of human health and agricultural production, for the conservation of endangered species and for the testing of numerous theories in population genetics. However, little is known due to the limitation and tremendous cost of the previous estimation method (mutation-accumulation), and it has been argued that this is one of the most glaring gaps in the broad field of genetics. We propose to narrow this gap by accomplishing the following specific aims. We will 1) develop efficient experimental designs and powerful statistical methods to estimate U and the distribution parameters of deleterious mutation effects; 2) develop statistical methods to discriminate between the two long- standing rival hypotheses concerning the maintenance of genetic variability and inbreeding depression-namely, the dominance and overdominance hypotheses; 3) investigate the statistical properties of the methods developed/to be developed and test their robustness under a range of biologically plausible conditions and experimental designs; 4) investigate the optimal experimental design for mutation-accumulation experiments; 5) develop a use-friendly computer software package for empiricists to apply any of the estimation methods, whatever complex statistical and computational techniques are involved. The results from the proposed work will provide powerful and efficient experimental designs and statistical methods for estimating U, and the distribution of mutation effects in a broad range of taxa, and will provide useful and powerful tools for empiricists to characterize deleterious genomic mutations.